Due to their high stability in plasma and few side effects, an increasing number of antibodies are being used as pharmaceuticals. A conventional antibody targeting a soluble antigen binds the antigen in the plasma of the patient after injection and then stably persists in the form of an antibody-antigen complex until degradation. While a typical antibody has generally a long half-life (1-3 weeks), an antigen has a relatively short half-life of less than one day. An antigen in complex with an antibody therefore has a significantly longer half-life than the antigen alone. Consequently, the antigen concentration tends to increase after the injection of a conventional antibody. Such cases have been reported for antibodies targeting various soluble antigens, such as IL-6 (J Immunotoxicol. 2005, 3, 131-9. (NPL 1)), beta amyloid (MAbs. 2010 September-October; 2(5):576-88 (NPL 2)), MCP-1 (ARTHRITIS & RHEUMATISM 2006, 54, 2387-92 (NPL 3)), hepcidin (AAPS J. 2010, 12(4):646-57. (NPL 4)) and sIL-6 receptor (Blood. 2008 Nov. 15; 112(10):3959-64. (NPL 5)). Reports have described an approximately 10 to 1000-fold increase (depending of the antigen) of total plasma antigen concentration from the baseline upon antibody administration.
As such an increase of the total plasma antigen concentration is not desired, strategies for removing the antigen by a therapeutic antibody have been developed. One of these strategies is to dispose the antigen rapidly using a pH-dependent antigen binding antibody that has increased binding affinity to the neonatal Fc receptor for IgG (FcRn) (see e.g. PCT application no. PCT/JP2011/001888 (PTL 1)). The FcRn is a protein found in the membrane of many cells. An antibody with increased binding activity to FcRn at neutral pH will bind FcRn on the cell surface, whereby the receptor with the antibody is internalized into the cells in a vesicle. As the pH in the interior of the vesicle is gradually decreased, the antigen will dissociate from the pH-dependent antigen binding antibody, owing to its low affinity in acidic pH. The dissociated antigen is then degraded while the FcRn and bound antibody are recycled back to the surface of the cells before degradation. Accordingly, a pH-dependent antigen binding antibody having increased binding activity to FcRn at neutral pH can be used to remove an antigen from plasma and decrease its concentration in plasma.
Previous studies have also demonstrated that Fc-engineering to increase the binding affinity to FcRn at acidic pH can also improve the endosomal recycling efficiency and the pharmacokinetics of the antibody. For example, M252Y/S254T/T256E (YTE) variant (J Biol Chem, 2006, 281:23514-23524. (NPL 6)), M428L/N434S (LS) variant (Nat Biotechnol, 2010 28:157-159. (NPL 7)), T250Q/M428L (J Immunol. 2006, 176(1):346-56. (NPL 8)) and N434H variant (Clinical Pharmacology & Therapeutics (2011) 89(2):283-290. (NPL 9)) showed improvement in half-life relative to native IgG1.
However, such substitutions have also the risk of altering properties of the antibody that are important for the development of a therapeutic antibody such as the antibody's stability, immunogenicity, aggregation behavior and binding affinity for pre-existing antibodies (e.g. rheumatoid factor). It is therefore the main objective of the present invention to provide a modified FcRn-binding domain which not only enhances the clearance of an antibody but also meets the criteria for developing a therapeutic antigen-binding molecule. These developability criteria are in particular high stability, low immunogenicity, low percentage of aggregates, and low binding affinity for pre-existing anti-drug antibodies (ADA).
Prior art documents related to the present invention are shown below. All documents cited in this specification are incorporated herein by reference.